This application is a 371 of PCT/DK99/00119, filed on Mar. 9, 1999.
The present invention relates to novel 5-heteroaryl substituted indoles having high affinity for xcex11-adrenoceptors. According to their activity at xcex11-adrenoceptors, the compounds of the invention are considered useful for the treatment of diseases or disorders responsive to xcex11-adrenoceptor antagonists. Further, as the compounds are selective xcex11-adrenoceptor ligands they may be particularly useful as PET or SPECT ligands.
U.S. Pat. No. 4,710,500 discloses in general optionally 5-substituted indole derivatives having the general formula: 
The compounds may be substituted in position 5 with a substituent selected from halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, CF3, lower alkylsulphonyl, amino, lower alkylamino and lower di-alkyamino. The compounds are claimed to be potent and long-lasting dopamine antagonists, and accordingly useful for the treatment of psychoses, and additionally to be strong 5-HT antagonists indicating effects in the treatment of negative symptoms of schizophrenia and depression and for the treatment of cardiovascular diseases.
The use of sertindole having the formula 
an antipsychotic is specifically claimed in EP-A2-0 392 959.
This type of compounds has also been shown to be useful for the treatment of a range of other disorders including anxiety (WO 92/00070), cognitive disorders (WO 92/15303), abuse (WO 92/15302) and hypertension (WO 92/15301).
WO 92/15301 discloses compounds having affinity for the xcex11-adrenoceptor. The compounds of the present invention differ from the compounds disclosed therein by being substituted in position 5 with an aromatic heterocyclic ring.
The compounds disclosed in WO 92/15301 are not selective for the xcex11-adrenoceptor.
Interest in the development of xcex11-adrenoceptor antagonists has primarily focused on therapeutics for the treatment of Benign Prostatic Hyperplacia (BPH) and cardiovascular diseases (Hieble et al., Exp. Opin. Invest. Drugs, 1997, 6, 3657). Prazosin is the prototype of an xcex11-adrenoceptor antagonist which has very potent peripherally effects. Prazosin has also in some animal models indicated effects in the central nervous system, although prazosin is considered to have poor CNS penetration. Until now, no xcex11-adrenoceptor selective antagonist with good CNS penetration to the human brain has been described.
Evidence exists indicating that blockade of xcex11-adrenoceptor neurotransmission could be beneficial in the treatment of schizophrenia. Most classical antipsychotics including clozapine bind potently to xcex11-adrenoceptors labelled with [3H]prazosin or [3H]WB-4101. Some studies seem to indicate a central role of the xcex11-component for the atypical profile of clozapine (Baldessarini, et al., Br. J. Psychiatry, 1992, 160, 12-16 and Prinssen, et al., Eur. J. Pharmacol., 1994, 262, 167-170). Further, repeated co-administration of prazosin and haloperidol was found to reduce the effect of haloperidol on the firing of dopamine neurons in nigrostriatal areas, suggesting that the combination would be effective as antipsychotic treatment without producing extrapyramidal side effects (EPS) (Chiodo, et al., J. Neurosci. 1985, 3, 2539-2544).
It has also been suggested that centrally acting xcex11-adrenoceptor antagonists will have antimanic effects while corresponding agonists would be beneficial for the treatment of depression (Lipinsky, et al., Life Sciences, 1987, 40, 1947-1963).
Labelled compounds of the present invention are considered to be valuable PET (positron emission tomography) ligands and SPECT ligands due to their selectivity for xcex11-adrenoceptors.
Finally, it is well established that xcex11-adrenoceptor antagonists acting peripherally are useful for the treatment of benign prostatic hyperplacia, hypertension and cardiac arrhytrnias and for the reduction of intra ocular pressure.
Accordingly, the present invention relates to 5-substituted indole derivatives having the general formula: 
wherein
Het is a five or six membered aromatic heterocyclic ring containing at least one nitrogen as a ring member, and optionally substituted with one or more substituents selected from C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio and hydroxy;n is 0, or 1;
G is N, C, or CH; the dotted line meaning a bond when G is C, and the dotted line meaning no bond when G is CH, or N;
Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, C1-6-alkyl, C1-6-alkoxy, hydroxy, trifluoromethyl and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
R2, R3, R4 and R5 are independently selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, C1-6-alkylamino and C1-6-dialkylamino;
R6 is hydrogen, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkyl, or C2-6-alkenyl, optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twentyfour carbon atoms inclusive, or R6 is a group of the formula II or III: 
wherein m is an integer from 2-6;
W is O, or S;
U is N or CH;
Z is xe2x80x94(CH2)pxe2x80x94, p being 2 or 3, or Z is xe2x80x94CHxe2x95x90CHxe2x80x94 or 1,2-phenylene optionally substituted with halogen or trifluoromethyl, or Z is xe2x80x94COCH2xe2x80x94 or xe2x80x94CSCH2xe2x80x94;
V is O, S, CH2, or NR9, wherein R9 is hydrogen, C1-6-alkyl or C2-6-alkenyl optionally substituted with one or two hydroxy groups, or a C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl group; X is N, C, or CH; Y is N, C, or CH; provided at least one of X and Y is N; and R7 is hydrogen, or C1-6-alkyl;
or a pharmaceutically acceptable acid addition salt thereof.
In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention relates to the use of a compound of formula I as defined above or an acid addition salt thereof and optionally a second pharmaceutically active ingredient for the manufacture of a pharmaceutical preparation for the treatment of a disorder or disease responsive to antagonism of xcex11-adrenoceptor.
Diseases or disorders responsive to antagonism of xcex11-adrenoceptors includes psychosis, mania, benign prostatic hyperplacia, hypertension, cardiac arrhytmias and reduction of intra ocular pressure.
In still another aspect, the present invention relates to the use of a compound of formula I as above and optionally a second agent having antipsychotic activity for the preparation of a medicament for the treatment of psychosis.
In a further aspect, the invention relates to a method for the treatment of a disorder or disease responsive to antagonism of xcex11-adrenoceptors in a mammal comprising administering a compound of formula I as above and optionally a second pharmaceutically active ingredient to said mammal.
In still another aspect, the present invention relates to a method for the treatment of psychosis in a mammal comprising administering a compound of formula I as above and optionally a second agent having antipsychotic activity to said mammal.
Finally, the present invention relates to radio-labelled compounds of formula I and the use thereof in various biological assays and PET- or SPECT studies.